Exp Brain Res (1992) 92:165-172

Experimental BrainResearch 9 Springer-Verlag1992

Metabolic brain pattern of sustained auditory discrimination Robert M. Cohen, William E. Semple, Michael Gross, Anna C. King, and Thomas E. Nordahl Section on Clinical Brain Imaging, Bldg 10/4N317, LCM, NIMH, IRP, 9000 RockvillePike, Bethesda, MD 20892-1000, USA Received July 3, 1991 / Accepted June 3, 1992

Summary. Positron emission tomography of [18F]-2fluorodeoxyglucose was used to assess the functional brain activity of normal subjects while performing auditory discrimination (CPT), while receiving an identical set of tones as in CPT, but with the instructions that they were background noise, or while at rest. The present study: (1) confirms earlier findings of an association between the functional activity of the right midprefrontal cortex and the performance of auditory discrimination, (2) localizes this increase in right prefrontal cortex activity to the middle prefrontal gyrus; and (3) provides a framework of specific testable hypotheses for the evaluation of the importance of certain limbic and paralimbic areas in the biological determination of sustained attention to be addressed in future studies. The framework accounts for the now confirmed finding that the middle cingulate has lower metabolic activity in CPT than at rest, and new findings of alterations in temporal lobe processing of tones in response to attention. Key words: Attention - Basal ganglia Cingulate - Temporal lobe - Human

Frontal cortex-

Introduction One of the unsolved central issues in the neurobiology of behavior is how an organism maintains goal-directed behavior. It is generally assumed that an organism decides to execute a plan to achieve its goals on the basis of an evaluation of current external (sensory derived stimuli) and internal input (drives, motivations, expectations). However, once an organism has begun motoric activity to achieve a specific end, it is probable that external if not internal input will change. Nevertheless, it is important that an organism favor follow-through or else risk never reaching any of its goals. Moreover, the Correspondence to:

R.M. Cohen

organism is more likely to succeed if it is able to direct its attention to stimuli that are important to achieving this end. Failure to satisfactorily carry out this aspect of behavior is a frequent manifestation of a variety of neuropsychiatric disorders, including those resulting from frontal lobe lesions, and schizophrenia (Mesulam 1985). In order to obtain a laboratory model of this process, we were interested in the functional localization of the ability to perform continuously auditory discrimination (CPT) in humans. In an earlier study (Cohen et al. 1988a), we compared the regional cerebral metabolic rates, obtained by positron emission tomography study of [18F]-2-fluoro-2-deoxy-D-glucose (FDG-PET) accumulation, of normal subjects performing CPT to those at rest (REST) or receiving "meaningless" intermittent electric shock. Higher metabolic rates were found in those regions of the right middle prefrontal cortex located 6 cm above the canthomeatal line (CM) and lower metabolic rates in an area of the middle cingulate, with a trend for lower rates in a superior posterior parietal cortex area. Moreover, there was a direct relationship observed between metabolic rates in these midprefrontal cortex regions and the accuracy of a subject's CPT, suggesting that this region was an important biological determinant of sustained attention. In studying medication-free schizophrenic and manic-depressive patients, even those who performed the task as well as normal subjects, metabolism was lower in the midprefrontal cortex and unrelated to performance (Cohen et al. 1987, 1989). We were interested in extending these findings by improving the technical aspects of the study, and by adding the important control condition of subjects listening to the identical tones as in the CPT condition, but given instruction to ignore the tones (TONES condition). Our initial studies (Cohen et al. 1987, 1988a, 1989), performed on an Ortec ECAT II tomograph with 1.75 cm in plane resolution, permitted the acquisition of only a single axial plane of data at a time. Thus, in practice, a total of only seven axial planes were obtained from each subject. To facilitate the completion of the already

166 l e n g t h y scan p r o c e d u r e , t r a n s m i s s i o n scans were o m i t t e d a n d a calculated a t t e n u a t i o n c o r r e c t i o n was used, b a s e d o n a n ellipse p o s i t i o n e d a r o u n d the p e r i m e t e r o f the subject's i m a g e d b r a i n slice. I n c o n t r a s t , in this extension, we were able to scan subjects with a t o m o g r a p h o f 5 - 6 m m r e s o l u t i o n t h a t permits the s i m u l t a n e o u s acquisit i o n o f seven slices. I n total, we were able to o b t a i n 28 axial slices o f glucose m e t a b o l i c d a t a a n d acquire a t r a n s m i s s i o n scan for a n empirical a t t e n u a t i o n c o r r e c t i o n in c o n s i d e r a b l y less time t h a n was r e q u i r e d for subjects in the earlier scan study. These technical i m p r o v e m e n t s are o f p a r t i c u l a r imp o r t a n c e for the accurate d e t e r m i n a t i o n o f m e t a b o l i c rates in those b r a i n regions t h a t are small in size a n d / o r located in the inferior parts o f the b r a i n . T h e accurate q u a n t i f i c a t i o n o f these regions, m o s t n o t a b l y the caudate, p u t a m e n , h i p p o c a m p u s , a n d o r b i t o f r o n t a l regions, are n o t o n l y o f i m p o r t a n c e because o f their p r o p o s e d roles in a t t e n t i o n , b u t also because o f their significance in the p a t h o p h y s i o l o g y o f n e u r o p s y c h i a t r i c disorders a n d their t r e a t m e n t , e.g., P a r k i n s o n ' s disease, H u n t i n g t o n ' s disease, A l z h e i m e r ' s disease, obsessive-compulsive disorder, a n d schizophrenia.

Materials and methods

Subjects The 55 normal volunteers for these studies were recruited through advertisements in a National Institutes of Health (NIH) newspaper and then carefully screened to eliminate individuals with significant medical or psychiatric problems. Twelve subjects, 4 men and 8 women with a mean age of 34.14- 12.9 and a range of 18-57 years, participated in the resting state (REST); 8 subjects, 5 men and 3 women with a mean age of 29.8 + 9.6 and a range of 21-51 years, participated in the TONES condition; and 35 subjects, 20 men and 15 women with a mean age of 36.14-11.3 and a range of 22-58 years, participated in the CPT condition.

tinued for some 30 min following injection. During this period, serial arterial blood samples were taken from the arm (generally the right) for quantification of FDG uptake. Twenty-eight slices (four scans containing 7 slices each) were obtained from each subject starting at 5-8 mm above the plane parallel to the CM. The interslice interval was approximately 3.8 mm. Scans were performed with a Scanditronix scanner of 5-6 mm full width half-maximum in-plane resolution and 11 mm axial resolution. A transmission scan utilizing a ring source of lSF was obtained on each subject for the purposes of attenuation correction. During the entire procedure, the subject's head was stabilized through the use of a hexalite plastic mask, which was first heated, then molded to the contours of their head and face, and subsequently fixed to the scanner headrest.

Data analysis Raw pixel values (counts) were converted to glucose metabolic rate (GMR) in milligrams per 100 g tissue per minute (Sokoloff et al. 1977; Phelps et al. 1979; Brooks 1982). As previously described (Cohen et al. 1988a), metabolic data were extracted from 60 regions of interest in five standard planes (see Fig. 1). Anatomical structures are judged as contained within these regions on the basis of the atlas of Matsui and Hirano (1978). Two raters, unaware of task condition, processed all scans. The interrater reliability was high (unpublished data). The averages of the glucose metabolic rates of the raters for each of the regions were used in the analyses. The data were transformed by a standardization procedure similar in principle to the "reference ratio" or "landscape method" (Metter et al. 1984). Operationally, this calls for dividing a subject's regional absolute glucose metabolic rate by the mean absolute metabolic rate for all cortical regions sampled in that same subject. The transformation is designed to minimize the effects of individual variation in global glucose metabolism on regional comparisons (Clark et al. 1985). As all the data were tested for statistical significance by multiple t-tests of this variable, the standardized regional metabolic rate or reference ratio, we will simply refer to this variable as the regional metabolic rate and refer to the untransformed variable as the absolute regional glucose metabolic rate.

Behavioral tasks

Performance measures

The CPT and TONES conditions each consisted of a random series of 500-Hz tones of 1 s duration and 2 s intertone interval. Tones were delivered to both ears through headphones with an intensity of 67, 75, or 86 dB, measured at the earphone-ear interface. In the CPT condition, the subject was instructed to press the left hand-held response button when the lowest volume tone was detected. The tones in both conditions were presented in successive 5-min blocks for 35 rain following FDG injection. Each CPT subject is presented with a total of 220 targets and 440 distractors. Subjects in the CPT condition were first trained to a criterion approximating 18 of 20 correct identifications in the hour immediately preceding FDG injection. For the TONES condition each subject was presented with the same tones as in the CPT condition, but was instructed that the tones were meaningless or background noise. In REST subjects had their eyes patched and wore headphones, as did the subjects in the CPT and TONES conditions. The wearing of headphones resulted in a moderate attenuation of extraneous auditory stimuli.

The measures of performance directly obtained for each subject are the number of targets correctly identified (hits) and the number of distractors incorrectly identified as targets (false alarms). In our earlier study, we examined the relationship between both hits and false alarms with respect only to those regions with metabolic rates that significantly differed between the REST and CPT groups. Because the coefficient of variation was much greater for false alarms than hits we were not surprised that our initial attempts to observe biological determinants of performance were more successful using false alarms as the behavioral measures. However, correlations observed between regional brain activity and false alarms might reflect an association between a region's functional activity and a subject's response bias rather than an association to performance accuracy if those subjects producing the fewest false alarms were also producing the fewest hits. Although there was no significant positive correlation between hits and false alarms, we, nevertheless, created a new "secondary" performance parameter log [hits/(false alarms+ 1)]. The measure was intended to : (1) correct for differing response biases; (2) be as model independent as possible; (3) allow us to include subjects that did not produce any false alarms; and (4) provide a favorable statistical quality in comparison to an untransformed ratio. Our secondary accuracy measure is correlated to the more usual model-dependent signal analysis parameter d' (r = 0.75 P < 0.0001).

P E T scan procedure Subjects participating in CPT or TONES began their task several minutes prior to the injection of a 5-mCi dose of FDG and con-

167 Left and Medial

o ..^

rl""Jllk:~

Rolandic Left Left Posterior Posterior Parietal Medial Left Frontal j

Anterior / _ Frontal ~

B

Me;i= Frontal

Right

y,vianl ~

,i/=

Medial

ccip tal

3

A

D

Arte:ior Temp,=.ralTe'rndpdorea, Temporal Temporal

Fig. l. Schematic representation of regions sampled in the left and right hemispheres (Left, Right) is shown. Regions labeled as Medial, although sampled from the medial portion of the cortex, are

represented where possible as incomplete boxes on the lateral surface. The boxes outlinedby dashedlines are sampled from the surface of the frontal cortex medial to the temporal lobe

Statistical analysis

choice reduces the discrepancy in the quantification of G M R s between these two scanners that differ markedly in resolution. We also hoped to improve on the interpretation of the regional metabolic findings by the addition o f a second control group. This second control group received the same auditory stimuli ( T O N E S ) as the CPT group, but with the instructions that the tones were merely background noise. As in our initial study (Cohen et al. 1988a), the global gray matter G M R s in our current study did not vary across behavior conditions (REST, 10.40 4- 1.43 ; T O N E S , 10.27+1.68; CPT, 9.784-1.36), but regional differences in activity were apparent. The three ROIs, the right anterior and posterior frontal cortex ( C R A F and C R P F ) regions of plane C, and the cingulate cortex, which statistically differed between C P T and R E S T in our first study, again differed in the new comparison, with the C-plane right frontal cortex regions higher and the cingulate lower in C P T (See Fig. 1 and Table 1). A fourth region, the superior posterior medial parietal cortex, a region whose metabolic rate might have been contingent on behavioral condition, i.e., there was a statistical trend in the first study for the metabolic rate in that region to be lower in subjects performing C P T c o m p a r e d with subjects at REST, was not observed to be significantly involved in this new study. However, because this region lies in the m o s t superior plane (plane A), it m a y be particularly prone to mismatch between the two studies. In the original study, we examined associations between auditory discrimination performance and cerebral metabolism in those brain regions demonstrating condition-dependent metabolism. Because only the metabolism of the right anterior frontal region, plane C, was significantly correlated with performance, we assumed its functional importance to the maintenance of directed attention. In this study the correlation between m e t a b o -

The best statistical approach to the analysis of imaging data, and specifically PET data, has yet to be delineated. Although a number of different statistical approaches have been taken in the literature, few attempts at verification have been reported. The effects of behavior on FDG-PET studies are small in magnitude, generally less than 15 %. To obtain any statistical significance between behavioral tasks, standardized values (transformed data) are required. Using individual t-tests (multiple univariate tests) corrected for the large number of tests, e.g., the Bonferroni t-test, makes these tests relatively "powerless" to detect the small changes expected compared with the variance of the measures. However, the alternative to not analyzing the totality of PET data obtained is both ethically (radiation exposure of subjects) and economically unreasonable. Furthermore, the FDG-PET technique is most useful in comparison to other methodologies in understanding the interaction of all regions of the brain with a single determination. Thus, we decided to report the statistical significance of uncorrected univariate data, while remarking on the degree of certainty based on both replicability and consistency. Specifically,findings in regions that were not previously observed to be related to behavioral conditions should be considered exploratory in nature and to require future replication. It is worth noting that, because of a variety of computer problems, we were able to accurately assess the performance of only 24 of the 35 subjects performing CPT. As a result, analyses dependent upon behavioral data, e.g., false alarms have a somewhat reduced statistical power.

Results To replicate our earlier w o r k (Cohen et al. 1988a) comparing subjects performing C P T with their R E S T counterparts, the analysis of the new (Scanditronix) P E T data was designed to be consistent with that utilized to examine the older E C A T P E T data (see Materials and methods). This was achieved in part by making the size of the regions of interest (ROIs) relatively large, 45 R O I s were 1.96 cm 2 and 4 R O I s were 2.60 cmz. In principle, this

168

Table 1. Comparisons of the means (• SD) of the standardized regional glucose metabolic rates of normal controls performing auditory discrimination or at rest in the original and new PET studies Regions

Right anterior frontal (plane C) Right posterior frontal (plane C) Cingulate cortex Superior posterior medial parietal (plane A)

Original study REST

CPT

p values for means

1.004 • 0.053 1.007• 0.065 1.107• 1.133•

1.054 • 0.069 1.074:~0.071 1.042• 1.068 •

0.02 0.001 0.02 0.06

The regions listed in this table were the only ones, among the 60 evaluated, for which statistically significant differencesbetween the

Current study REST

CPT

p values for means

1.005 • 0.063 1.009• 1.122• 1.114•

1.059 + 0.075 1.078• 1.017•0.112 1.123•

0.030 0.010 0.005 NS

REST and CPT conditions were found in the original PET study NS, not significant

Exploratory analyses ,,
TONES). Interregional correlations (Table 3 and Fi9. 3). To limit type I error, we examined correlations only among brain regions already demonstrated to have significant condition-dependent metabolism. Moreover, because of the small number of subjects in the REST (n = 12) and

169 Table 2. Exploratory comparisons of the means ( • SD) of the standardized regional glucose metabolic rates of subjects in the REST, TONES, and CPT conditions Region of interest

Mean ( • SD) by task REST

Probability

TONES

CPT

TONES

CPT

CPT

VS

VS

VS

REST

REST

TONES

Cortex Anterior medial parietal (plane A) Left sylvian (plane C) Right sylvian (plane C) Left parietal (plane C) Left parietal-occipital (plane C) Left middle temporal (plane D) Right posterior temporal (plane D) Anterior medial frontal (plane E) Left hippocampal

1.002• 1.013• 1.024+0.105 1.033 • 0.078 0.890• 0.988 • 0.066 0.8654-0.060 0.962 • 0.056 0.829•

1.0764-0.091 1.007• 1.009• 0.984• 0.821• 0.080 1.065 • 0.064 0.935• 0.921• 0.085 0.779 • 0.036

1.006• 1.068 • 0.094 1.074• 1.033 • 0.059 0.892• 0.996 4- 0.060 0.879• 0.905 4- 0.056 0.781•

NS NS NS NS NS NS NS NS 0.03

NS NS NS NS NS NS NS 0.004 0.01

0.05 0.09 0.04 0.04 0.06 0.007 0.07 NS NS

Subcortical Left caudate Right caudate Left posterior putamen Right posterior putamen

1.0184-0.106 1.038• 1.0134-0.119 1.068•

1.1374-0.078 1.068• 1.0734-0.082 1.027i0.084

1.0004-0.108 0.9804-0.106 1.0004-0.102 0.982•

0.01 NS NS NS

NS NS NS 0.01

0.001 0.05 0.05 NS

Probability determined by two-tailed t-test Table 3. Comparisons of the Pearson product-moment metabolic rate correlations (Corr.) observed among selected brain regions in subjects performing CPT, in TONES, at REST, or in either REST or TONES condition Correlated regions

Interregional correlations REST

TONES

Corr.

P

Corr.

P

REST + TONES

CPT

Corr.

Corr.

P

P

Cingulate vs: Left caudate Right caudate Right anterior putamen Left middle temporal cortex (plane D)

-0.69 -0.75 -0.57 -0.31

0.01 0.005 0.05 NS

-0.59 -0.33 -0.65 -0.51

0.13 NS 0.08 NS

-0.62 -0.50 -0.67 -0.46

0.003 0.01 0.0001 0.04

+0.27 +0.07 +0.21 -0.01

NS NS NS NS

Left middle temporal cortex (plane D) vs: Right anterior frontal cortex (plane C) Left caudate

-0.48 +0.54

0.11 0.07

-0.64 +0.29

0.09 NS

-0.47 +0.63

0.04 0.003

-0.50 +0.16

0.03 NS

Anterior medial frontal cortex (plane E) vs: Left hippocampus Right hippocampus

+0.64 +0.49

0.02 0.10

+0.61 +0.58

0.11 0.13

+0.64 +0.51

0.003 0.02

-0.19 -0.07

NS NS

T O N E S (n = 8) c o n d i t i o n s , i n t e r r e g i o n a l c o r r e l a t i o n s in these t w o c o n d i t i o n s a r e c o n s i d e r e d reliable o n l y w h e n c o n s i s t e n c y is o b s e r v e d a c r o s s b o t h c o n d i t i o n s a n d in a c o m b i n e d g r o u p o f R E S T a n d T O N E S subjects ( R E S T + T O N E S , n -- 20). W h e n a l a r g e r n u m b e r o f subjects h a s been s c a n n e d a n d their m e t a b o l i c rates ext r a c t e d , a m o r e s o p h i s t i c a t e d analysis t a k i n g into a c c o u n t the m u l t i p l e d e p e n d e n c e o f the m e t a b o l i c d a t a will be r e p o r t e d . T h e c i n g u l a t e m e t a b o l i c rates in the R E S T , T O N E S , a n d the R E S T p l u s T O N E S g r o u p s , b u t n o t in the C P T g r o u p , were inversely a s s o c i a t e d w i t h the m e t a b o l i c r a t e s o f the left a n d r i g h t c a u d a t e , r i g h t a n t e r i o r p u t a m e n , a n d the D L M T R O I s . D i r e c t c o r r e l a t i o n s were o b s e r v e d in R E S T , T O N E S , a n d R E S T plus T O N E S g r o u p s , b u t n o t in the C P T g r o u p , w i t h r e s p e c t to the left c a u d a t e a n d D L M T ; a n d

1 ,3

0 REST A TONES

0

0

A

A

q-J

1.1

A

c-

oO

CD

1.0 p = -0.638 (p < 0.003)

0,9

I

0,8

I

0,9

I

0

I

A ~

I

I

1,0 1.1 1,2 1,3 L e f t Caudate Fig. 3. Scatterplot demonstrating the negative association between the metabolic rate of the middle cingulate region with the metabolic rate of the left caudate region in subjects participating in either the TONES or REST conditions

170 with respect to the left and right hippocampal regions and the orbitofrontal region (the anterior medial frontal cortex region of plane E). CRAF was inversely associated with D L M T under all conditions. Discussion

The present study: (1) confirms earlier findings of an association between the functional activity of the right midprefrontal cortex and the performance of CPT; (2) localizes that activity to the middle prefrontal gyrus; and (3) provides a framework of specific testable hypotheses for the evaluation of the importance of certain limbic and paralimbic areas in the biological determination of sustained attention, to be addressed in future studies. First, nearly identical mean metabolic rate differences in the midprefrontal cortex between the CPT and REST subjects and an even higher positive association between metabolic activity in this area and performance were observed in this new study. Additional importance is attached to the new study because it was performed on independently recruited subjects, on a PET scanner of substantially improved resolution, and with the improved quantitation afforded by the use of arterial blood sampling and an empirically determined attenuation correction. Second, the findings that nearly identical differences are noted when another control group consisting of subjects who receive the same set of auditory stimuli as the CPT subjects, but who were told that the tones they will be hearing are merely background noise, also strengthen the interpretation of the earlier work. The use of this new control group establishes the likelihood that the part of the middle cingulate gyrus (our cingulate ROI is drawn from a superior plane) previously determined to have a lower metabolic rate in CPT than in REST probably relates more closely to the presentation of repetitive auditory stimuli than the ability to perform sustained attention. There was no direct relationship between metabolism in the cingulate and performance, and equivalent differences were observed in TONES as in CPT when both were compared with REST. Possibly because of the use of a higher resolution scanner with an empirically derived attenuation correction, two other brain regions, containing the hippocampus and an area of the inferior medial frontal cortex, are also found to have lower metabolic rates related to the presentation of auditory stimuli regardless of instruction set (Table 2). It is important to note that these latter findings must be considered exploratory in nature. Because our earlier experiment using cruder measurement techniques did not demonstrate these regions to be different, another hypothesis testing study needs to be undertaken to demonstrate the importance of these findings. Included in these exploratory findings are those suggesting the importance of the basal ganglia and regions in the lateral temporal and parietal lobes to CPT (Table 2). Illustratively, the findings in the lateral temporal cortex imply that there is a functional activation of DLMT

in response to the auditory signals delivered in TONES, but that this response is altered in response to attention (CPT). The interregional correlational analysis (Table 3) is consistent with this conclusion, as it reveals expected directional associations between DLMT and CRAF and the cingulate cortex. Further support derives from the findings of recent blood flow studies, conducted with PET at the National Institute of Mental Health (NIMH), in which DLMT appeared to be an important biological determinant of auditory processing. Using an identical anatomic template to that used in the current study, D L M T was found to be activated in normals performing tasks requiring either extensive phonetic or syntactic processing of auditory signals and in a test of tonal memory (Rumsey et al. 1992 and personal communication). Therefore, replication of these lateral temporal lobe, basal ganglia, and parietal cortex findings would indicate a complex role for these regions in the biological determination of CPT. The fact that many of these newly "identified" regions, however, show condition-dependent interregional correlations (Table 3) makes it possible to construct a hypothetical framework for understanding how the middle prefrontal gyrus may orchestrate the biological determination of sustained attention.

A heuristic account

The significance of the prefrontal cortex in the determination of normal sustained attention and abnormal attention as observed in neuropsychiatric disorders has been reviewed (Mesulam 1981; Stuss and Benson 1986; Cohen et al. 1988a, b). As formulated by GoldmanRakic (1987), the prefrontal cortex has the capacity to inhibit most behavior in order to allow the execution of single acts. That the prefrontal cortex may serve the organism in this particular role finds support in the PET data. The negative correlation of false alarms with midprefrontal cortex metabolism (CRAF) observed is equivalent (except sign) to a positive correlation of distractors-false alarms, with CRAF metabolism. Assuming the subject is attending, the quantity distractors-false alarms represents the number of suppressed or inhibited responses. Paralimbic and limbic structures. But what are the specific anatomic connections that allow this regulation with respect to sustained attention? Speculatively, we propose that an appropriate place to begin is with those ROIs in the PET data that have lower metabolism in both the TONES and CPT conditions than in REST. These ROIs include areas of the middle cingulate cortex, the medial orbitofrontal cortex, hippocampus, and parahippocampal regions. The regions are all part of the the limbic or paralimbic structures of the brain. The paralimbic association areas (Pandya and Yeterian 1986) are situated between the limbic structures and the sensory association regions, with direct connections not only to these regions but also interconnections among themselves. Both aria-

171 tomic and physiological studies have made both the limbic and paralimbic regions prime candidates for relating information to motivational and emotional states. The interregional correlations among some of these areas, e.g., the orbitofrontal cortex and hippocampal regions and in REST and TONES may reflect their functional linkage. The cingulate and basal ganglia, and cingulate and DLMT share an inverse association in REST and TONES but not in CPT. Part of the process of performing the auditory discrimination continuously, therefore, may involve uncoupling the basal ganglia and temporal cortex from cingulate cortex influence as well from each other. The midprefrontal cortex is a good candidate for effecting this uncoupling. Specifically, CRAF metabolic rate was found to be inversely correlated to the metabolic rate in DLMT, providing support for the hypothesis that the midprefrontal cortex may influence auditory processing in this region so as to efficiently serve the goal of the organism with respect to tonal input. That the prefrontal cortex might be the most important structure for setting the organism's priorities for goals without immediate gain would be consistent with considerable experimental evidence (Goldman-Rakic 1987). Moreover, based on the work of Pardo et al. (1991), it is likely that the right middle prefrontal gyrus plays a similar role in visual and somatosensory vigilance tasks to that in auditory ones, including semantic processing of words (Petersen et al. 1988). This hypothetical formulation is consistent with other proposals in which the basal ganglia is the site at which different brain regions compete to gain control of the motor system (Passingham 1987). For example, although input from the limbic regions might connect to a different area of the striatum than those from the prefrontal cortex, short intrastriatal connections could, through lateral inhibition, lead to coherent behavior, placing basal ganglia functional activity under the control of either the prefrontal cortex or the limbic system, depending upon priorities (Rolls 1990). Specifically, with respect to attention, dysfunction in the basal ganglia and its dopamine input in animals leads to unilateral neglect (Marshall et al. 1971 ; Ljundberg and Ungerstedt 1976; Dunnett and Iversen 1982; Carli et al. 1985; Amalric and Koob 1987; Mogenson 1987; Brown and Robbins 1989). Moreover, electrophysiological data is suggestive of caudate neuron involvement in complex integrations such as those that occur when motor output is contingent upon sensory input (Rolls et al. 1983; Nishino et al. 1984; Ohye et al. 1987). The alternative interpretation that the shift to lower metabolism in the basal ganglia in response to the instructional set, i.e., the change from ignoring the tones (TONES) to responding to them (CPT), results from the actual execution of the motor response appears unlikely given that higher basal ganglia metabolic rates have been reported for motor tasks (Roland et al. 1982; Mazziotta and Phelps 1986). Thus, we have come to the somewhat unorthodox conclusion that regions demonstrating decreases in metabolic rate in association with task performance may be telling us something about how the "ac-

tivated" region of the middle prefrontal gyrus may be working to induce sustained attention. O c c a m ' s razor. Further meaning may be attributed to the observation of condition-dependent reduced regional metabolic rates. In our original study (Cohen et al. 1988a), we interpreted the lower activity we observed in the cingulate cortex in CPT as a reflection of an improved signal-to-noise ratio for the processing of external stimuli. If Occam's razor is to be applied, we must assume that the regional changes in the medial orbitofrontal and hippocampal regions, if replicated, must result from a similar mechanism. However, the fact that these decreases also occur in TONES raises some doubt that this is the sole interpretation. Perhaps the subjects at rest are the ones that have the most active paralimbic and limbic area activities, because they are engaged in multiple associations that are relatively rich in emotional and cognitive content. Such mental activity would clearly contrast with the requirements of a subject who is concentrating on the discrimination of tones who would ideally wish to remain "empty-headed". We were drawn to this additional interpretation on the basis of the new data on the metabolic brain pattern of the TONES condition and the differences in interregional limbic and basal ganglia correlations in CPT compared with REST and TONES (see above). Posner and Petersen (1990) have come to similar conclusions based on their own work in attention and our earlier findings. If this explanation is correct it suggests that even the TONES condition may have been sufficient to disrupt these emotion- and cognitive-rich processes. Unfortunately, direct experimental evidence for the emptyheaded concept is lacking, as we did not systematically ascertain what the subjects were doing during the REST and TONES conditions.

References

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Metabolic brain pattern of sustained auditory discrimination.

Positron emission tomography of [18F]-2-fluorodeoxyglucose was used to assess the functional brain activity of normal subjects while performing audito...
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